This application addresses broad Challenge Area (05) Comparative Effectiveness Research and specific Challenge Topic, 05-AI-101: Accelerated Aging in Treated vs. Untreated HIV/AIDS. With the advent of HAART, life expectancy for HIV-infected persons may now extend for decades. As growing numbers of HIV-infected persons in the US are surviving into older ages, a shifting spectrum of disease towards age-associated non- AIDS conditions has been documented and an accelerated aging process has been hypothesized. Proposed is systematic investigation of the epidemiology and mechanisms of declines in physical function and of the development of frailty, recognized phenotypes for the aging process. Using longitudinal data collected in the AIDS Linked to the IntraVenous Experience (ALIVE) study for up to 7 years, we will define trajectories and identify demographic, behavioral, and clinical correlates of physical function decline and a frailty-related phenotype. Utilizing our extensive biological repository and building on prior mechanistic work which identified selected inflammatory genes involved in frailty, we will evaluate circulating inflammatory markers and inflammatory gene expression levels in participants with or without physical function declines using a nested case-control study design. We emphasize the evaluation of HAART, particularly the comparative effect of treatment interruptions or incomplete virologic suppression versus continuous or suppressive therapy respectively, in predicting decrements or improvements in physical function. The community-recruited ALIVE cohort represents an urban, predominantly African American population of both genders with significant risk factors for chronic diseases. Importantly, ALIVE includes at risk HIV-uninfected participants, providing an epidemiologically-appropriate comparison group to permit HIV-related effects on aging phenotypes to be separated from background effects among high-risk persons. Our proposal, which largely supports the immediate hiring of new personnel, represents an efficient, value-added research investment by performing highly focused investigations on participants nested within an existing HIV cohort. Results from these studies will inform the HIV research community on the rates of, predictors and mechanisms involved in physical function declines, which may eventually allow earlier identification and intervention to prevent accelerated aging among HIV-infected persons. PUBLIC HEALTH RELEVANCE: This application addresses broad Challenge Area (05) Comparative Effectiveness Research and specific Challenge Topic, 05-AI-101: Accelerated Aging in Treated vs. Untreated HIV/AIDS.